1. Field of the Invention
The present invention relates to a method for determining the concentration of an ion, atom or molecule bound in a complex.
2. Description of the Related Art
Numerous ions, atoms and molecules are not present in isolated form, but in the form of the most different complexes. This relates to ions, atoms and molecules both in the blood circulation of a patient and in the blood that is taken from the patient for the purpose of a certain blood treatment or patient treatment and has suitable complex agents added outside the body.
An example for the complexing of ions is so-called citrate anti-coagulated haemodialysis/haemofiltration. Here, a complexing of Ca++ ions of the blood takes place in the extra-corporal blood circulation by means of citrate in order to inhibit blood clotting during the treatment, above all during the blood/membrane contact in the dialyser.
Inhibition of blood clotting is required with most haemodialysis patients today. The standard is to use non-fractioned heparin that is infused into the arterial side of the extra-corporal hose system by a syringe pump. The use of both non-fractioned heparin and alternative anti-coagulants such as low-molecular-weight heparin or hirudin is problematic for some of the patients and for other extra-corporal blood therapies for the following reasons:
Anti-coagulation has a systemic effect (that is not only on membrane contact in the extra-corporal circulation, but in the whole body), which results in critical haemorrhage risk for some patients. In particular in the intensive medical area, 30 to 40% of patients are at risk of haemorrhage.
Some patients show incompatibility reactions such as heparin-induced thrombocytopenia which exclude the use of these anti-coagulants.
Adsorptive therapies (for example liver replacement therapy) can be incompatible with the use, for example, of heparin if this neutralises the binding points of the adsorber (provided for the adsorption of toxins).
An alternative which avoids the problems listed is regional clotting inhibition (only in the extra-corporal circulation, above all during the blood/membrane contact) by citrate. In this method shown in FIG. 1, the concentration of free calcium (Ca) is reduced by so much by the addition of tri-sodium citrate at the point in accordance with Pos. 1 in FIG. 1 that the clotting cascade is interrupted, with two citrate molecules in case forming a complex with three Ca ions. The use of Ca-free dialysate in accordance with Pos. 2 in FIG. 1 and the Ca withdrawal this causes also contributes to the concentration reduction. To avoid depletion of the body with respect to Ca and Mg (which is also bound by citrate), a further solution (see Pos. 3 in FIG. 1) containing Ca ions and Mg ions in an adapted concentration must be infused into the venous side of the extra-corporal circulation or into a separate venous entry.
Clinical studies [Morita Y, Johnson R W, Doren R E, Hall D S, “Regional anticoagulation during hemodialysis using citrate”. The American Journal of the Medical Sciences (1961); Janssen M J M F et al., “Citrate compared to low molecular weight heparin anticoagulation in chronic hemodialysis patients”, Kidney Int (1996) 49:806-813; Mehta R L, McDonald B R, Aguilar M M, Ward D M, “Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients”, Kidney Int (1990) 38:976-981] demonstrate that regional citrate anti-coagulation very effectively prevents blood clotting in the extra-corporal circulation. At the same time, an increased risk of haemorrhage for the patient is avoided. Citrate dialysis is therefore seen as an interesting, effective alternative to conventional heparin anti-coagulation for that part of the patient population in which—as described above—the use of heparin is disadvantageous or clearly contra-indicated.
Despite these clear therapeutic advantages, citrate anti-coagulation has only been used to a low extent up to now and not as an automated, standardised process. The reasons for this are:                1. The increased effort: in conventional dialysis, standard haemo-dialysis solution and a low amount of heparin is required. In citrate dialysis, three solutions are usually required: the haemo-dialysis solution free of Ca and Mg and adapted in the Na and bicarbonate content, the tri-sodium citrate solution and the Ca++/Mg++ solution.        2. Safety aspects in the dosing of the Ca++/Mg++ solution: if an incorrect dose is given here, a life-threatening situation can quickly arise (tetany, cardiac irregularity, cardiac arrest). Incorrect dosing can arise as a result of technical problems (e.g. failure of the pump, leaks, etc.), or by an incorrect determination of the Ca requirement.        3. Consequences of a supply of citrate or of the Ca3—Ci2 or Mg3—Ci2 complexes: metabolic alkalosis, non-physiological Ca concentration.        
The increased effort of the process can be limited by a suitable technical realisation; certain additional costs are quite justified in patients with heparin incompatibilities. The supply of citrate or of citrate complexes can be greatly reduced by efficient withdrawal via the membrane (use of a large-area high-flux filter, possibly in combination with post-dilution HDF). A low remaining supply can probably be tolerated; if not, it can also be estimated and compensated by suitable modelling of the dialysis process and of the metabolisation of the complexes.
A citrate anti-coagulated dialysis method is known from WO 91/06326. Tri-sodium citrate is added to the arterial supply line of the extra-corporal blood circulation as the anti-coagulant, with the added amount of tri-sodium citrate per time unit only being adapted to the blood stream rate in the extra-corporal circulation. If the blood stream rate increases or falls, the addition rate of tri-sodium citrate is also increased or lowered respectively. The calcium ion concentration of the patient blood is not monitored in a close-meshed manner here, but determined in fairly large time intervals by blood samples. Since a close-meshed or continuous monitoring of the calcium concentration in the blood of the patient is missing and since the amount of added citrate is oriented only on the blood flow rate and not on the calcium level of the patient, it cannot be reliably precluded in this previously known method that calcium values result in the patient's blood which are non-physiological and which can accordingly bring about life-threatening consequences for the patient.
While ion-sensitive sensors are known by means of which the calcium ion concentration or the magnesium ion concentration in the blood of a patient can also be determined in small time intervals, the use of a sensor on the blood side is, however, disadvantageous and therefore undesirable due to a possible toxicity, as a result of sterility demands and for cost reasons.
It can also be necessary to make a concentration determination of ions, atoms or molecules bound in complexes in other applications than dialysis. Even under the assumption that ion-sensitive sensors could be used without disadvantages for the patient, their use in the determination of the concentration of complexed ions frequently does not deliver any results, or any results which can be utilised, since the properties of the ion present in the complex do not allow a meaningful measurement.